1-109715019-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000851.4(GSTM5):c.433C>T(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,614,210 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (104 hom.)
• Consequence: GSTM5 NM_000851.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.398

Genes affected

GSTM5 (HGNC:4637): (glutathione S-transferase mu 5) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004138142).
• BP6: Variant 1-109715019-C-T is Benign according to our data. Variant chr1-109715019-C-T is described in ClinVar as [Benign]. Clinvar id is 769521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM5	NM_000851.4	c.433C>T	p.Arg145Trp	missense_variant	6/8	ENST00000256593.8
GSTM5	XM_005270784.5	c.433C>T	p.Arg145Trp	missense_variant	7/9
GSTM5	XM_005270785.5	c.121C>T	p.Arg41Trp	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM5	ENST00000256593.8	c.433C>T	p.Arg145Trp	missense_variant	6/8	1	NM_000851.4	P3

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152206 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00949 AC: 2387 AN: 251488 Hom.: 100 AF XY: 0.00704 AC XY: 957 AN XY: 135922

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00212 AC: 3103 AN: 1461886 Hom.: 104 Cov.: 31 AF XY: 0.00178 AC XY: 1295 AN XY: 727248

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.0583

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00441

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152324 Hom.: 8 Cov.: 33 AF XY: 0.00385 AC XY: 287 AN XY: 74476

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00627

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00743 AC: 902

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	0.022
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.27	T
Polyphen		0.60	.;P;.
Vest4		0.25, 0.26
MVP		0.26
MPC		0.13
ClinPred		0.13	T
GERP RS		-0.15
Varity_R		0.22
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140499099; hg19: chr1-110257641;